A Study of Belcesiran in Patients With AATLD (ESTRELLA)
|
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04764448 |
|
Recruitment Status :
Active, not recruiting
First Posted : February 21, 2021
Last Update Posted : March 28, 2024
|
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
This is a multiple dose, randomized, placebo-controlled, double-blind study of belcesiran to evaluate the safety, tolerability, PK, and PD in adult patients with PiZZ AATD-associated liver disease (AATLD).
The study will be conducted in 3 separate cohorts. A total of up to 16 participants may be enrolled in Cohort 1 and 2. A total number of 30 subjects will be enrolled in cohort 3. The 3 cohorts are differentiated by the duration of the treatment period, the number of doses administered, and the timing of the second liver biopsy.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Alpha 1-Antitrypsin Deficiency | Drug: Belcesiran Other: Placebo | Phase 2 |
AATD-associated liver disease is a progressive condition resulting in liver fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. The lack of functional alpha-1 antitrypsin (AAT) in individuals with the PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity of neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism may be addressed by use of intravenous augmentation therapy, which aims to substitute the missing AAT by infusing alpha-1 proteinase inhibitor (A1PI), purified from pooled human plasma.
While augmentation therapy can address the loss of AAT in the lung, no treatment exists for the associated liver disease.
Given the severity of the disease, with approximately 10% of affected patients developing liver cirrhosis and a subgroup of those patients in need of liver transplantation, and the lack of an effective treatment that addresses the toxic hepatic "gain-of-function" mechanism, there is an urgent unmet medical need to develop a therapy that can help this particular patient population.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 46 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Triple (Participant, Investigator, Outcomes Assessor) |
| Masking Description: | Double blind |
| Primary Purpose: | Other |
| Official Title: | A Phase 2, Randomized, Double-blind, Placebo-Controlled Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease |
| Actual Study Start Date : | February 12, 2021 |
| Actual Primary Completion Date : | December 8, 2023 |
| Estimated Study Completion Date : | December 1, 2026 |
| Arm | Intervention/treatment |
|---|---|
| Experimental: Belcesiran Cohort 1 |
Drug: Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants. |
| Placebo Comparator: Placebo Cohort 1 |
Other: Placebo
Comparator: Placebo Cohort 1 Administered sterile normal saline (0.9% NaCl) matching volume of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants. |
| Experimental: Belcesiran Cohort 2 |
Drug: Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants. |
| Placebo Comparator: Placebo Cohort 2 |
Other: Placebo
Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants. |
| Experimental: Belcesiran Cohort 3 |
Drug: Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks. |
| Placebo Comparator: Placebo Cohort 3 |
Other: Placebo
Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks. |
- The incidence and nature of treatment emergent adverse events (TEAE) [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in pulmonary function tests (PFTs): Forced Vital Capacity (FVC) [ Time Frame: Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in pulmonary function tests (PFTs): Forced Expiratory Volume in One Second (FEV1) [ Time Frame: Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in pulmonary function tests (PFTs): Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in 12-lead ECGs: Heart Rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in 12-lead ECGs: Ventricular Rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in 12-lead ECGs: RR interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in 12-lead ECGs: PR interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in 12-lead ECGs: QRS interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in 12-lead ECGs: QT interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in 12-lead ECGs: corrected QT interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- The incidence of clinically significant physical examination (PE) findings [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in vital sign measurements: temperature [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in vital sign measurements: pulse rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in vital sign measurements: respiratory rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in vital sign measurements: blood pressure [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in clinical laboratory tests: clinical chemistry [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in clinical laboratory tests: hematology [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in clinical laboratory tests: Coagulation [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in clinical laboratory tests: Serum AFP [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in clinical laboratory tests: Total complement hemolytic activity CH50 [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in clinical laboratory tests: C-reactive protein (CRP) [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline in clinical laboratory tests: Antidrug antibodies [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from Baseline in serum AAT concentration [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
- Change from baseline to Week 24 in serum Z-AAT protein levels [ Time Frame: up to 24 weeks (Cohort 3) ]
- Change from baseline to Week 24 in liver Z-AAT liver protein levels [ Time Frame: up to 24 weeks (Cohort 3) ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 18 to 75 years, inclusive, at the time of consent.
- Documented diagnosis of PiZZ-type alpha-1 antitrypsin deficiency, confirmed by genotyping. Historical genotyping data may be used, if available.
- AATD-associated liver disease documented by liver biopsy at Screening.
- Consent to undergo paired liver biopsies.
- Lung, renal and liver function within acceptable limits
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria:
- History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type alpha-1 antitrypsin deficiency.
- Child-Pugh Score B or C.
- History of one single severe exacerbation of underlying lung disease in the year prior to randomization.
- History of clinically significant respiratory infections (including pneumonia and lower respiratory tract infections), as determined by the Investigator, in the 3 months prior to screening
- Use of an RNAi drug at any time.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04764448
Show 23 study locations
| Study Director: | Thomas Bowman, MD | Dicerna Pharmaceuticals / Novo Nordisk |
| Responsible Party: | Dicerna Pharmaceuticals, Inc., a Novo Nordisk company |
| ClinicalTrials.gov Identifier: | NCT04764448 |
| Other Study ID Numbers: |
DCR-A1AT-201 |
| First Posted: | February 21, 2021 Key Record Dates |
| Last Update Posted: | March 28, 2024 |
| Last Verified: | March 2024 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | Yes |
|
Alpha 1-Antitrypsin Deficiency Liver Diseases Digestive System Diseases Lung Diseases Respiratory Tract Diseases |
Genetic Diseases, Inborn Subcutaneous Emphysema Emphysema Pathologic Processes |